Eisai Company, Ltd. ONTAK(R) (denileukin diftitox) Achieves 49.1% Overall Response Rate in Phase III Trial of Cutaneous T-Cell Lymphoma (CTCL)

CHICAGO, June 4 /PRNewswire/ -- Preliminary results of the largest randomized, placebo-controlled clinical trial ever conducted in patients with cutaneous T-cell lymphoma (CTCL) showed that ONTAK was more than twice as effective as placebo in eliciting a clinical response in patients with CTCL. [Abstract number 8026] The primary endpoint of this study was to measure the total percentage of documented responders based on improvement in tumor burden in skin, blood and lymph nodes in each treatment arm, confirmed over three consecutive cycles. Secondary endpoints included progression-free survival, which is defined as the time from the first day of treatment to the first observation of tumor progression or death due to any cause up to 30 days after the last dose of study drug. The results were presented here today at the annual meeting of the American Society of Clinical Oncology (ASCO).

ONTAK is indicated for the treatment of patients with persistent or recurrent cutaneous T-cell lymphoma (CTCL) whose malignant cells express the CD25 component of the IL-2 receptor. The safety and efficacy of denileukin diftitox in patients with CTCL whose malignant cells do not express the CD25 component of the IL-2 receptor have not been examined. ONTAK was granted accelerated approval in February 1999.

CTCL is a rare disease in which certain cells of the lymph system known as T lymphocytes become cancerous and affect the skin. CTCL can progress to the lymph nodes, spleen, liver and other organs. About 10% of CTCL sufferers will experience progressive disease with lymph node and/or internal involvement with serious complications. There is no known cure for CTCL.

"The preliminary results of this study show that ONTAK achieved its primary endpoint, which was to prove superiority versus placebo in eliciting a clinical response in patients with CTCL," commented Miles Prince, MD, Chair of Cancer Services at Peter MacCallum Cancer Centre, Melbourne, Australia, and a lead investigator of this trial. "This study also showed an extension in progression-free survival for these patients, a secondary trial endpoint."

In the trial, 144 patients with CTCL, whose malignant cells expressed the CD25 component of the IL-2 receptor, were randomized to receive either of two doses of ONTAK [9 mcg/kg/day (n=45) or 18 mcg g/kg/day (n=55)] or placebo (n=44) for up to eight cycles of therapy (median cycles for all patients = 6; range for all patients is 1-11). Per protocol, eligible patients had received three or less prior treatments and had stages Ia to III disease. Both ONTAK doses were superior to placebo in a dose-dependent fashion. The response rate was 37.8% (95% confidence interval: 23.8, 53.5) with the lower ONTAK dose (p=0.0297 vs. placebo), 49.1% (95% confidence interval: 35.4, 62.9) with the higher ONTAK dose (p=0.0015 vs. placebo) compared to 15.9% (95% confidence interval: 6.6, 30.1) with placebo. Whereas 11.1% of patients on the lower ONTAK dose and 9.1% of those on the higher ONTAK dose had either a complete response to treatment or clinical complete response, only 2.3% of patients receiving placebo experienced this benefit. The proportion of patients experiencing progressive disease were 26.7% for the lower ONTAK dose, 16.4% for the higher ONTAK dose and 52.3% for placebo. Both ONTAK doses were also better than placebo with regard to median time of progression-free survival: 794 days (95% confidence interval: 155.0, not estimable) for the lower ONTAK dose, greater than 971 days (median not reached) for the higher ONTAK dose, and 124 days (95% confidence interval: 92.0, 176.0) for placebo.

The most common adverse events in the ONTAK-treated patients included fever (56%), nausea (54%), fatigue (45%), rigors (45%), headache (27%), vomiting (25%), peripheral edema (23%), rash (22%), diarrhea (22%), myalgia (19%), cough (19%), asthenia (18%), pruritus (17%), back pain (17%), anorexia (15%), arthralgia (14%) and upper respiratory tract infection (13%).

The percentage of patients reporting serious adverse events (SAEs) was higher for ONTAK than for placebo. Drug-related SAEs in ONTAK-treated patients were capillary leak syndrome (4%), dehydration (4%), hypotension (3%), fever (3%), hypoalbuminemia (2%), skin disorder (2%), chest pain (2%), vascular fragility (2%), fatigue (2%), hypersensitivity (2%), myocardial ischemia (1%), urinary tract infection (1%), blood pressure decreased (1%), joint stiffness (1%), myalgia (1%), carpel tunnel syndrome (1%), loss of consciousness (1%), respiratory distress (1%), dermatitis exfoliative (1%), erythema (1%), and rash generalized (1%). The frequency of SAEs decreased after the first two cycles of treatment. The percentage of patients overall who discontinued the study due to an adverse event was higher in the ONTAK group (20.0%) compared with the placebo group (9.1%).

"We are pleased that research continues with ONTAK in the treatment of patients with CTCL," said Judy Jones, Executive Director of the Cutaneous Lymphoma Foundation. "This study reflects Eisai's ongoing commitment to satisfying unmet medical needs in oncology, particularly in CTCL, a form of cancer for which there is no cure."

About ONTAK(R) (denileukin diftitox)

ONTAK is a genetically engineered fusion toxin protein consisting of the amino acid sequences for the enzymatically-active portion of diphtheria toxin fused to the sequence of human interleukin-2, resulting in a molecule that is cytotoxic for cells bearing the target IL-2 receptor expressed on malignant cells.

ONTAK is indicated for the treatment of patients with persistent or recurrent cutaneous T-cell lymphoma (CTCL) whose malignant cells express the CD25 component of the IL-2 receptor. The safety and efficacy of denileukin diftitox in patients with CTCL whose malignant cells do not express the CD25 component of the IL-2 receptor have not been examined.

Important Safety Information

WARNING: Only physicians experienced in the use of antineoplastic therapy and management of patients with cancer should use ONTAK (denileukin diftitox). Patients treated with denileukin diftitox must be managed in a facility equipped and staffed for cardiopulmonary resuscitation and where the patient can be closely monitored for an appropriate period based on his or her health status.

WARNINGS Acute Hypersensitivity-type Reactions: -- Acute hypersensitivity reactions were reported in 98 of 143 patients (69%) during or within 24 hours of ONTAK infusion; approximately half of the events occurred on the first day of dosing regardless of the treatment cycle. -- The constellation of symptoms included one or more of the following, defined as the incidence (%) in these 98 patients: hypotension (50%), back pain (30%), dyspnea (28%), vasodilation (28%), rash (25%), chest pain or tightness (24%), tachycardia (12%), dysphagia or laryngismus (5%), syncope (3%), allergic reaction (1%) or anaphylaxis (1%). -- These events were severe in 2% of patients. Death during infusion has been reported. Vascular Leak Syndrome: -- This syndrome, characterized by 2 or more of the following 3 symptoms (hypotension, edema, hypoalbuminemia) was reported in 27% (38/143) of patients in the clinical studies. -- Six percent (8/143) of patients were hospitalized for the management of these symptoms. -- The onset of symptoms in patients with vascular leak syndrome was delayed, usually occurring within the first two weeks of infusion; symptoms may persist or worsen after the cessation of denileukin diftitox. -- Cases of vascular (capillary) leak with a fatal outcome have been reported. -- Special caution should be taken in patients with preexisting cardiovascular disease (See ADVERSE REACTIONS, Cardiovascular System).

Weight, edema, blood pressure and serum albumin levels should be carefully monitored on an outpatient basis. This syndrome is usually self-limited and treatment should be used only if clinically indicated. The type of treatment will depend on whether edema or hypotension is the primary clinical problem. Preexisting low serum albumin levels appear to predict and may predispose patients to the syndrome (see PRECAUTIONS, Laboratory Tests).

Visual Loss: -- Loss of visual acuity, usually with loss of color vision, with or without retinal pigment mottling has been reported following administration of ONTAK. Recovery was reported in some of the affected patients; however, most patients reported persistent visual impairment.

ADVERSE REACTIONS

The most commonly reported adverse events associated with the use of ONTAK therapy (n=143 patients) include hypoalbuminemia (83%), chills/fever (81%), asthenia (66%), nausea/vomiting (64%), transaminase increase (61%), infection (48%), pain (48%), edema (47%), hypotension (36%), anorexia (36%), and rash (34%).

Post Marketing

The following adverse reactions have been identified during post approval use of ONTAK. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relation to drug exposure.

Special Senses: See WARNINGS: Visual Loss

For detailed safety information and full prescribing information about ONTAK(R) (denileukin diftitox), please see attached prescribing information or visit www.eisai.com.

About Eisai Inc.

Eisai Inc. is a U.S. pharmaceutical subsidiary of Eisai Co., Ltd., a research-based human health care (hhc) company that discovers, develops and markets products throughout the world. Eisai focuses its efforts in three therapeutic areas: neurology, gastrointestinal disorders and oncology/critical care. Established in 1995 and ranked among the top-20 U.S. pharmaceutical companies (based on retail sales), Eisai Inc. began marketing its first product in the United States in 1997 and has rapidly grown to become an integrated pharmaceutical business with sales of approximately $2.6 billion in fiscal year 2006 (year ended March 31, 2007). Eisai Inc. employs approximately 1,500 people at its headquarters in Woodcliff Lake, NJ, at its state-of-the- art pharmaceutical production and formulation research and development facility in Research Triangle Park, NC, and in the field. For more information about Eisai, please visit www.eisai.com.

Eisai Inc.

CONTACT: Judee Shuler of Eisai Inc., +1-201-746-2241, During ASCO, +1-908-337-2540

Web site: http://www.eisai.com/